In addition to well-known forms of cell death, such as apoptosis, necrosis, autophagy and the like, a new form of cell death, methuosis, has been revealed in recent years. The hallmark of this form of death is a displacement of normal cytoplasm by large fluid-filled vacuoles generated by macropinocytotic vesicles or macropinosomes inside the cell. Consequently, the cell loses its metabolic capacity and its membrane integrity without cell shrinkage and nuclear fragmentation associated with apoptosis, also significantly different from necrosis and autophagy (Maltese et al. Methuosis: nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am J Pathol. 2014; 184 (6): 1630-42). Owing to the different mechanism of methuosis from that of cell apoptosis, a drug causing cell death by methuosis could overcome the resistance of tumor cells to antiapoptotic drugs or drugs acting through other mechanisms, and therefore open a new venue for the development of therapies against cancer (Robinson et al. Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death. J Med Chem. 2012; 55 (5):1940-56; Kitambi et al. Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule. Cell. 2014; 157(2):313-28; Trabbic et al. Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity. J Med Chem. 2015; 58 (5):2489-512).
Vimentin is a major intermediate filament protein expressed in mesenchymal cells, including the cells of connective tissue, muscle, vascular endothelium and blood. Highly conservative evolution and dynamic expression during different developmental stages suggest that vimentin is physiologically important. Together with microtubules and actin microfilaments, intermediate filaments form a cytoskeleton. In addition to the function of improving mechanical strength of cells so as to sustain cellular shape, cytoskeleton integrity and orderly spatial distribution of subcellular structure, vimentin can also regulate the function of integrin, so as to affect cellular adhesion and migration; collaborate with dynein such as microtubules, microfilaments and the like to affect membrane transport of vesicules; and act as a scaffold for receptor and protein kinase so as to affect signal transduction, etc (Ivaska et al. Novel functions of vimentin in cell adhesion, migration, and signaling. Exp Cell Res. 2007; 313 (10):2050-62).
Vimentin is closely related with lipid metabolism, having control over transport of low density lipoprotein (LDL)-derived cholesterol from lysosome to locations for esterification thereof (Sarria et al. A functional role for vimentin intermediate filaments in the metabolism of lipoprotein-derived cholesterol in human SW-13 cells. J Biol Chem. 1992 Sep. 25; 267 (27): 19455-63). In view of the high expression of vimentin in the cells of vascular endothelium and smooth muscle, targeting vimentin could be a strategy that is worth trying for the development of new drugs for treating or preventing cardiovascular diseases such as atherosclerosis. Vimentin expression is a marker of epithelial-mesenchymal transition (EMT). EMT is not only an essential mechanism in normal physiological processes such as embryonic development and tissue repair, but also an indispensable route in pathological processes such as organ fibrosis, and tumor formation and progression (Gonzalez et al. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7 (344): re8). Therefore, by using vimentin as a target to intervene in the EMT process, it's possible to develop a new drug for promoting tissue regeneration, inhibiting organ degeneration, treating tissue fibrosis, preventing tumor metastasis, etc (Davis et al. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014; 35(9): 479-88).